International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 2: T2 substaging and prostate cancer volume.
The 2009 International Society of Urological Pathology consensus conference in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to the substaging of pT2 prostate cancers according to the TNM 2002/2010 system, reporting of tumor size/volume and zonal location of prostate cancers were coordinated by working group 2. A survey circulated before the consensus conference demonstrated that 74% of the 157 participants considered pT2 substaging of prostate cancer to be of clinical and/or academic relevance. The survey also revealed a considerable variation in the frequency of reporting of pT2b substage prostate cancer, which was likely a consequence of the variable methodologies used to distinguish pT2a from pT2b tumors. Overview of the literature indicates that current pT2 substaging criteria lack clinical relevance and the majority (65.5%) of conference attendees wished to discontinue pT2 substaging. Therefore, the consensus was that reporting of pT2 substages should, at present, be optional. Several studies have shown that prostate cancer volume is significantly correlated with other clinicopathological features, including Gleason score and extraprostatic extension of tumor; however, most studies fail to demonstrate this to have prognostic significance on multivariate analysis. Consensus was reached with regard to the reporting of some quantitative measure of the volume of tumor in a prostatectomy specimen, without prescribing a specific methodology. Incorporation of the zonal and/or anterior location of the dominant/index tumor in the pathology report was accepted by most participants, but a formal definition of the identifying features of the dominant/index tumor remained undecided.


Analysis of SERF in Thai blood donors.
The Cromer blood group system consists of nine high-prevalence and three low-prevalence antigens carried on decay-accelerating factor (DAF). We recently described one of these Cromer highprevalence antigens,SERF, the absence of which was found in a Thai woman. The lack of SERF antigen in this proband was associated with a substitution of nucleotide 647C>T in exon 5 of DAF, which is predicted to be a change of proline to leucine at amino acid position 182 in short consensus repeat (SCR) 3 of DAF. This study reports on PCR-RFLP analysis of the SERF allele with BstNI restriction endonuclease on more than one thousand Thai blood donor samples. One new donor homozygous (647T) and 21 donors heterozygous (647C/T) for the SERF allele were found. Among this cohort of random Thai blood donors, the SERF allele frequency was 1.1 percent. Thus, like other alleles in the Cromer blood group system, SERF is found in a certain ethnic group.


New approach in diagnosis of bile duct disease with ultrasound and magnetic resonance imaging.
Advances in technology have made possible the clinical application of magnetic resonance cholangiography, endoscopic, intra-operative and laparoscopic ultrasound in the study of the biliary tree, in addition to conventional magnetic resonance imaging and transabdominal ultrasound. The role of the conventional, as well as the newer techniques, in the diagnosis of bile duct disease and the limitations and pros and cons of each technique, will be the subject of the present discussion.


Intra- and intermolecular domain interactions of the C-terminal GTPase effector domain of the multimeric dynamin-like GTPase Drp1.
Mammalian Drp1 is a dynamin-like GTPase required for mitochondrial fission. Although it exists primarily as a cytosolic homo-tetramer in vivo, it can also self-assemble into higher order structures on the mitochondrial outer membrane, where it is required for proper mitochondrial division. Functional studies and sequence comparisons have revealed four different structural domains in Drp1, comprising N-terminal GTP-binding, middle, insert B, and C-terminal GTPase effector (GED) domains. Here we describe an intramolecular interaction within Drp1 between the GED and the N-terminal GTP-binding and middle domains. A point mutation (K679A) within the C-terminal GED domain inhibits this intramolecular association, without affecting the formation of Drp1 tetramers or the intermolecular associations among isolated C-terminal domains. Mutant Drp1 K679A exhibits impaired GTPase activity, and when overexpressed in mammalian cells it decreases mitochondrial division. Sedimentation experiments indicate that the K679A mutation either increases Drp1 complex formation or, more likely, decreases complex disassembly as compared with wild-type Drp1. Taken together, these data suggest that the C-terminal GED domain is important for stimulation of GTPase activity, formation and stability of higher order complexes, and efficient mitochondrial division.


Safe clinical practice for patients hospitalised in a suicidal crisis: a study protocol for a qualitative case study.
Suicide prevention in psychiatric care is arguably complex and incompletely understood as a patient safety issue. A resilient healthcare approach provides perspectives through which to understand this complexity by understanding everyday clinical practice. By including suicidal patients and healthcare professionals as sources of knowledge, a deeper understanding of what constitutes safe clinical practice can be achieved. This planned study aims to adopt the perspective of resilient healthcare to provide a deeper understanding of safe clinical practice for suicidal patients in psychiatric inpatient care. It will describe the experienced components and conditions of safe clinical practice and the experienced practice of patient safety. The study will apply a descriptive case study approach consisting of qualitative semistructured interviews and focus groups. The data sources are hospitalised patients in a suicidal crisis and healthcare professionals in clinical practice. This study was approved by the Regional Ethics Committee (2016/34). The results will be disseminated through scientific articles, a PhD dissertation, and national and international conferences. These findings can generate knowledge to be integrated into the practice of safety for suicidal inpatients in Norway and to improve the feasibility of patient safety measures. Theoretical generalisations can be drawn regarding safe clinical practice by taking into account the experiences of patients and healthcare professionals. Thus, this study can inform the conceptual development of safe clinical practice for suicidal patients.


Performance analysis for a K-winners-take-all analog neural network: basic theory.
In a previous work, the authors proposed an analog Hopfield-type neural network that identified the K largest components of a list of real numbers. In this work, we identify computable restrictions on the parameters, in order that the network can repeatedly process lists, one after the other, at a given rate. A complete mathematical analysis gives analytical bounds for the time required in terms of circuit parameters, the length of the lists, and the relative separation of list elements. This allows practical setting of circuit parameters for required clocking times. The emphasis is on high gain functioning of each neuron. Numerical investigations show the accuracy of the theoretical predictions, and study the influence of various parameters on performance.


Effect of crew resource management training in a multidisciplinary obstetrical setting.
To assess the effect of a Crew Resource Management (CRM) intervention specifically designed to improve teamwork and communication skills in a multidisciplinary obstetrical setting. Design--A before-and-after cross-sectional study designed to assess participants' satisfaction, learning and change in behaviour, according to Kirkpatrick's evaluation framework for training programmes. Setting--Labour and delivery units of a large university-affiliated hospital. Participants--Two hundred and thirty nine midwives, nurses, physicians and technicians from the department of anaesthesia, obstetrics and paediatrics. Intervention--All participants took part in a CRM-based training programme specifically designed to improve teamwork and communication skills. Principal measures of outcome-We assessed participants' satisfaction by means of a 10-item standardized questionnaire. A 36-item survey was administered before and after the course to assess participants' learning. Behavioural change was assessed by a 57-item safety attitude questionnaire measuring staff's change in attitude to safety over 1 year of programme implementation. Most participants valued the experience highly and 63-90% rated their level of satisfaction as being very high. Except for seven items, the 36-item survey testing participants' learning demonstrated a significant change (P<0.05) towards better knowledge of teamwork and shared decision making after the training programme. Over the year of observation, there was a positive change in the team and safety climate in the hospital [odds ratio (OR) 2.9, 95% confidence interval (CI) (1.3-6.3) to OR 4.7, 95% CI (1.2-17.2)]. **There was also improved stress recognition [OR 2.4, 95% CI (1.2-4.8) to OR 3.0, 95% CI (1.0-8.8)]. The implementation of a training programme based on CRM in a multidisciplinary obstetrical setting is well accepted and contributes to a significant improvement in interprofessional teamwork.


The SIRT3 activator ganoderic acid D regulates airway mucin MUC5AC expression via the NRF2/GPX4 pathway.
The expression of MUC5AC, a highly prevalent airway mucin, is regulated by stimulatory factors such as oxidative stress. Ganoderic acid D (GAD) activates mitochondrial deacetylase SIRT3. SIRT3 regulates mitochondrial function through deacetylation of mitochondrial proteins, thereby playing a significant role in alleviating oxidative stress-related diseases. Therefore, this study aimed to investigate the mechanisms and rationale underlying the regulation of MUC5AC expression by GAD. Human airway epithelial cells (NCI-H292) were exposed to pyocyanin (PCN) to establish an in vitro cell model of airway mucus hypersecretion. The expression of SIRT3, MUC5AC, and NRF2 pathway proteins in cells was assessed. Cellular mitochondrial morphology and oxidative stress markers were analyzed. C57BL/6 mice were induced with Pseudomonas aeruginosa (PA) to establish an in vivo mouse model of airway mucus hypersecretion. The expression of SIRT3 and MUC5AC in the airways was examined. In addition, the differential expression of target genes in the airway epithelial tissues of patients with chronic obstructive pulmonary disease (COPD) was analyzed using publicly available databases. The results revealed a significant upregulation of MUC5AC expression and a significant downregulation of SIRT3 expression in relation to airway mucus hypersecretion. GAD inhibited the overexpression of MUC5AC in PCN-induced NCI-H292 cells and PA-induced mouse airways by upregulating SIRT3. GAD activated the NRF2/GPX4 pathway and inhibited PCN-induced oxidative stress and mitochondrial morphological changes in NCI-H292 cells. However, ML385 inhibited the regulatory effects of GAD on MUC5AC expression. The SIRT3 activator GAD downregulated MUC5AC expression, potentially through activation of the NRF2/GPX4 pathway. Accordingly, GAD may be a potential treatment approach for airway mucus hypersecretions.


Arterial closure devices. A review.
The use of arterial closure devices in achieving haemostasis following arterial puncture has become increasingly popular. This review aims to provide an overview of the currently available closure devices, with an up-to-date summary of the supporting literature. The various devices have their advantages and disadvantages as well as differing mechanisms of actions. Technical aspects of deployment affect the learning curve and ease of use of individual devices. Some complications that arise are device specific where others are related to arterial punctures in general. When choosing a device, all these factors should be taken into account as well as differing clinical requirements and priorities. Most studies of arterial closure devices that are currently in use conclude that the safety profile of closure devices is comparable to manual compression. The literature does not show superiority of any particular device. Caution is advised in extrapolating evidence based on differing patient groups, as many of the study populations are heterogeneous. As physicians become more familiar with the use of closure devices, off-label applications of some devices have emerged, some of which need further evaluation. The ideal closure device should reduce complication rates compared to manual compression, be easy to use with a short learning curve, and have a high rate of deployment success. It should also be usable across a wide range of sheath sizes, not leave any permanent foreign body behind, reduce time to haemostasis and ambulation, allow immediate repuncture, improve patient comfort and be cost effective. In spite of the wide range of devices currently available there remains room for improvement.


Treatment of chronic airway diseases using nutraceuticals: Mechanistic insight.
Respiratory diseases, both acute and chronic, are reported to be the leading cause of morbidity and mortality, affecting millions of people globally, leading to high socio-economic burden for the society in the recent decades. Chronic inflammation and decline in lung function are the common symptoms of respiratory diseases. The current treatment strategies revolve around using appropriate anti-inflammatory agents and bronchodilators. A range of anti-inflammatory agents and bronchodilators are currently available in the market; however, the usage of such medications is limited due to the potential for various adverse effects. To cope with this issue, researchers have been exploring various novel, alternative therapeutic strategies that are safe and effective to treat respiratory diseases. Several studies have been reported on the possible links between food and food-derived products in combating various chronic inflammatory diseases. Nutraceuticals are examples of such food-derived products which are gaining much interest in terms of its usage for the well-being and better human health. As a consequence, intensive research is currently aimed at identifying novel nutraceuticals, and there is an emerging notion that nutraceuticals can have a positive impact in various respiratory diseases. In this review, we discuss the efficacy of nutraceuticals in altering the various cellular and molecular mechanisms involved in mitigating the symptoms of respiratory diseases.


Systemic Th17 response in the presence of periodontal inflammation.
The relationship between periodontitis and the pathogenesis of other inflammatory diseases, such as diabetes, rheumatoid arthritis and obesity has been an important topic of study in recent decades. The Th17 pathway plays a significant role in how local inflammation can influence systemic inflammation in the absence of systemic pathology. To determine Th17 biased-cells in systemically healthy patients in the presence of generalized chronic periodontitis. A total of 28 patients were recruited without systemic inflammatory pathology, which was determined by clinical history, the Health Assessment Questionnaire (HAQ) and rheumatoid factor detection. Of these patients, 13 were diagnosed as healthy/gingivitis (H/G) and 15 as generalized chronic periodontitis (GCP). Th17 (CD4+CD161+) cells and Th17IL23R+ (CD4+CD161+IL-23R+) cells were quantified by flow cytometry, based on the total cells and on the lymphocyte region, termed the "enriched population" (50,000 events for each). The percentages of Th17 cells of the H/G and periodontitis groups were similar on total cells and enriched population (19 vs 21.8; p=4.134 and 19.6 vs 21.8; p=0.55). However, Th17IL23R+ cells differ significantly between periodontally healthy patients and generalized chronic periodontitis patients in both total cell (0.22% vs 0.65%; p=0.0004) and enriched populations (0.2% vs 0.75%; p=0.0266). GCP patients (otherwise systemically healthy) were characterized by increased Th17-proinflammatory cell phenotype positive for the IL-23 receptor in peripheral blood. The proportion of Th17 cells that are negative for the IL-23 receptor in the peripheral blood of systemically healthy patients seemed to be unaffected by the presence or absence of chronic periodontitis.


Modulation of 5-fluorouracil by 5-ethyl-2'-deoxyuridine on cell lines expressing different dihydropyrimidine dehydrogenase activities.
The purpose of the present study was to clarify the significance of the inhibition of dihydropyrimidine dehydrogenase (DPD) in the modulation of 5-fluorouracil (5-FU) action by 5-ethyl-2'-deoxyuridine (EUdR). Four human cell lines, which differed in their susceptibility to 5-FU and in their DPD activity, were selected as biological objects. Several other enzymes of pyrimidine metabolism, i.e. thymidylate synthase (TS), thymidine kinase (TK) and pyrimidine nucleoside phosphorylase (PNP), which might be involved in the 5-FU action were also studied to elucidate their potential role in the modulation of 5-FU cytotoxicity. Two out of the four cell lines, i.e. COLO1 and SW620, showed low (57 and 28 pmol/min/mg protein) and the other two cell lines, i.e. CAL51 and CAL33, showed high (235 and 184 pmol/min/mg protein) DPD activity, respectively. In our study, contrary to our expectation, no correlation between the DPD and TS activity of the cell lines and their 5-FU sensitivity could be observed. EUdR alone was cytotoxic only on CAL33 cells in a concentration below 1 mM (IC50=194 microM) which might be due to the high TK activity (857 pmol/min/mg protein) measured in this cell line, favoring the formation of the phosphorylated nucleotides EdUMP and EdUTP indispensable for the inhibition of TS and DNA polymerase, respectively. Surprisingly, although EUdR by metabolizing to EUra was able to reduce the high activity of DPD in CAL33 and CAL51 cells by 47 and 55%, respectively, no potentiation of the 5-FU action occurred on these cell lines. On the contrary, enhancement of the 5-FU cytotoxicity was demonstrated on COLO1 and SW620 cells with low DPD activity. Our findings suggest that the 5-FU modulatory action of EUdR may be directed on other molecular targets than DPD as well, i.e. the augmentation of TS inhibition by EdUMP as demonstrated on SW620 cells might be one of these mechanisms.


Same patient, new stone composition: amprenavir urinary stone.
We report here the first case to add amprenavir to the growing list of antiretroviral drugs associated with urinary stones. The first reported case of a nelfinavir urinary stone was reported in 2002 in a 37-year-old HIV-infected woman. In September 2007, the same female patient was referred to our department with recent onset of right flank pain and recurrent urinary tract infections. Abdominal computed tomography revealed three obstructing stones in the distal right ureter, another stone in the right renal pelvis with hydronephrosis and a stone in the left kidney. After stone retrieval, analysis of the stone by liquid chromatography with mass spectrometry revealed a stone composition of 95% unmodified amprenavir and 5% ritonavir.


Results of en bloc resection for bronchogenic carcinoma with chest wall invasion.
Lung cancer invading the chest wall without lymph node metastasis has recently been downstaged to stage IIb. To validate this reclassification, we reviewed our experience with en bloc lung and chest wall resection for bronchogenic carcinoma. From February 1985 to November 1999, 95 en bloc lung and chest wall resections were performed on 94 patients (62 men and 32 women). The median age was 66 years (range, 38-93 years). Pancoast tumors were excluded. Factors that may affect survival were analyzed with univariate analysis, and factors found to be significant univariately were analyzed multivariately to determine whether the significant association remained after adjusting for other significant factors. Presenting symptoms included chest wall pain in 42 patients, cough in 17 patients, and "other" in 16 patients. Twenty patients were asymptomatic. Ninety-two patients were current or former smokers (median pack-years, 50; range, 8-150 pack-years). Seventy-five lobectomies, 12 pneumonectomies, 5 bilobectomies, 2 wedge excisions, and 1 segmentectomy were performed. The number of ribs resected ranged from 1 to 5 (median, 3). Sixty-one patients required chest wall reconstruction (prostheses in 60 and bovine pericardium in 1). Operative morbidity and mortality were 44.2% and 6.3%, respectively. Sixty-five cancers were classified as T3 N0 M0, 16 as T3 N1 M0, and 14 as T3 N2 M0. Squamous cell carcinoma was present in 56 tumors, adenocarcinoma in 25, large cell carcinoma in 11, and "other" in 3. Follow-up was complete in 86 (96.6%) of 89 operative survivors and ranged from 1 month to 15 years (median, 19 months). Overall 5-year actuarial survival was 38.7%. Five-year survival for patients with stage IIb disease (T3 N0 M0) was 44.3% compared with only 26.3% for those with stage IIIa disease (T3 N1 M0 or T3 N2 M0, P =.0082). Women had a better 5-year survival than men (52.9% vs 31.0%, P =.0122). The best 5-year survival was observed in women with stage IIb disease (61.2%). All other variables (age, tumor size, histopathology, forced expiratory volume in 1 second, extent of operation, depth of invasion, and adjuvant therapy) did not significantly affect survival. En bloc resection of lung cancer invading the chest wall is safe but associated with significant morbidity. Long-term survival is stage and sex dependent. The best survival is observed in women who have T3 N0 M0 disease (stage IIb).


Angiogenesis in the hollow fiber tumor model influences drug delivery to tumor cells: implications for anticancer drug screening programs.
The National Cancer Institute uses the hollow fiber assay as part of its screening program for anticancer drug discovery. Angiogenesis to hollow fibers implanted s.c. has not been reported, thereby raising concerns about the efficiency of drug delivery and its subsequent effects on chemosensitivity. By extending postimplantation times beyond the 6-day period presently used, extensive vascular networks develop, resulting in both increased delivery and chemosensitivity to doxorubicin. This study suggests that present protocols used to evaluate compounds may produce false negative results, and additional studies to determine the predictive value of the assay are required.


Research Review: What do we know about psychopathic traits in children?
Research on the topic of child psychopathy has advanced over the past decade increasing what we know. This qualitative review examines the research base for child psychopathy and emphasizes its three dimensions: grandiose-manipulative, callous-unemotional, and daring-impulsive. Literature is reviewed addressing the cognitive, emotional, motivational, personality, parenting, and biological correlates. Support has emerged for the phenotypic construct of child psychopathy, while questions remain regarding definitional issues and key external correlates (e.g., reward and punishment processing, parenting, molecular genetics, brain imaging). While the construct appears to be valid, future work should broaden its focus from callous unemotional traits to all three dimensions of the construct, enhance measurement precision, and examine dimension interactions. Such research could have important implications for CD specification for future versions of the DSM and ICD and speed etiological knowledge and clinical care for youth with conduct problems.


Anacardic Acid Reduces Acetylation of H4K12 in Mouse Oocytes during Vitrification.
Over the last years, vitrification has been widely used for oocyte cryopreservation, in animals and humans; however, it frequently causes minor and major epigenetic modifications. The effect of oocyte vitrification on levels of acetylation of histone H4 at lysine 12 (AcH4K12), and histone acetyltransferase (Hat) expression, was previously assessed; however, little is known about the inhibition of Hat expression during oocyte vitrification. This study evaluated the effect of anacardic acid (AA) as a Hat inhibitor on vitrified mouse oocytes. In this experimental study, 248 mouse oocytes at metaphase II (MII) stage were divided in three experimental groups namely, fresh control oocytes (which were not affected by vitrification), frozen/thawed oocytes (vitrified) and frozen/thawed oocytes pre-treated with AA (treatment). Out of 248 oocytes, 173 oocytes were selected and from them, 84 oocytes were vitrified without AA (vitrified group) and 89 oocytes were pretreated with AA, and then vitrified (treatment group). Fresh MII mouse oocytes were used as control group. Hat expression and AcH4K12 levels were assessed by using real-time quantitative polymerase chain reaction (PCR) and immunofluoresce staining, respectively. In addition, survival rate was determined in vitrified and treatment oocytes. Hat expression and AcH4K12 modification significantly increased [4.17 ± 1.27 (P≤0.001) and 97.57 ± 6.30 (P<0.001), respectively] in oocytes that were vitrified, compared to the fresh oocytes. After treatment with AA, the Hat mRNA expression and subsequently H4K12 acetylation levels were significantly reduced [0.12 ± 0.03 (P≤0.001) and 89.79 ± 3.20 (P≤0.05), respectively] in comparison to the vitrified group. However, the survival rate was not significantly different between the vitrified (90.47%) and treatment (91.01%) groups (P>0.05). The present study suggests that AA reduces vitrification risks caused by epigenetic modifications, but does not affect the quality of vitrification. In fact, AA as a Hat inhibitor was effective in reducing the acetylation levels of H4K12.


Hi-C profiling of cancer spheroids identifies 3D-growth-specific chromatin interactions in breast cancer endocrine resistance.
Organoids or spheroids have emerged as a physiologically relevant in vitro preclinical model to study patient-specific diseases. A recent study used spheroids of MCF10 cells to model breast cancer progression and identified targetable alterations more similar to those in vivo. Thus, it is practical and essential to explore and characterize the spheroids of the commonly used human breast cancer (BC) cells. In this study, we conducted Hi-C analyses in three-dimensional (3D) spheroids of MCF10A, MCF7 and MCF7TR cells and compared TADs and looping genes with those in 2D monolayers. Furthermore, we performed in silico functional analysis on 3D-growth-specific looping genes and to compare patient outcomes with or without endocrinal therapy. Finally, we performed 3C/RT-qPCR validations in 3D spheroids and 3D-FISH confirmations in organoids of breast cancer patient tissues. We found that chromatin structures have experienced drastic changes during the 3D culture growth of BC cells although there is not much change in the quantity of chromatin domains. We also observed that the strengths of looping genes were statistically different between 2D monolayers and 3D spheroids. We further identified novel 3D growth-specific looping genes within Hippo relevant pathways, of which two genes showed potential prognostic values in measuring the outcome of the endocrine treatment. We finally confirmed a few selected genes in Hippo relevant pathways with enhanced looping in organoids of breast cancer patient tissues. Hence, our work has provided significant insights into our understanding of 3D-growth-specific chromatin architecture in tamoxifen-resistant breast cancer. Our analyses suggest that the strengthened looping-mediated Hippo relevant pathways may contribute to endocrine therapy resistance in breast cancer patients.


Preventing stillbirths through improved antenatal recognition of pregnancies at risk due to fetal growth restriction.
Most stillbirths used to be categorized as 'unexplained' and were considered, by implication, unavoidable. Recent evidence indicates that they represent a combined challenge for public health and for clinical services. Independent case reviews have found that many deaths are associated with a failure to recognize risk factors and to afford them the appropriate standard of care. The majority of normally formed fetal deaths had preceding, unrecognized intrauterine growth failure. Improved training and adoption of standardized protocols has led to increased antenatal detection of fetal growth restriction, and this in turn has resulted in significant reductions in stillbirths in areas with high uptake of the training programme. A comprehensive, evidence-based growth assessment protocol (GAP) is currently being rolled out across the NHS to implement this strategy for stillbirth prevention.


Effect of frequency and conductivity on field penetration of electromagnetic hyperthermia applicators.
The field penetration of electromagnetic hyperthermia applicators in 2.5-29 g l-1 saline (NaCl) solutions over a range of frequencies is investigated. Calculated field penetration based on the current-element method agrees well with measurement at frequencies above about 100 MHz, but at lower frequencies measured field penetration becomes progressively less than calculated as conductivity is reduced. Experimental results and finite-difference time-domain (FDTD) method modelling show that the electromagnetic field produces circulating currents. The effect of these circulating currents on the heating pattern of the applicators should be considered when planning hyperthermia treatment.


What do we know about adenovirus in renal transplantation?
Adenoviruses are common pathogens that have the potential to cause opportunistic infections with significant morbidity and mortality in immunocompromised hosts. The significance of adenoviral infection and disease is incompletely known in the setting of kidney transplantation. Reported adenovirus infections in renal transplant recipients have typically manifested as hemorrhagic cystitis and tubulointerstitial nephritis, less severe diseases than often seen in other solid organ transplant recipients (i.e. pneumonia, hepatitis and enteritis). The prevalent adenovirus subgroups associated with cystitis and nephritis are B1 and B2 with the serotypes 7, 11, 34, 35. However, disseminated or severe adenovirus infections, including fatal cases, have been described in renal transplant recipients. There is uncertainty regarding monitoring of and treatment of this virus. Although not supported by randomized clinical trials, cidofovir is used for the treatment of adenovirus disease not responding to reduction of immunosuppression.


Intensive care for very elderly patients: outcome and risk factors for in-hospital mortality.
To evaluate outcome and risk factors, particularly the Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system, for in-hospital mortality in very elderly patients after admission to an intensive care unit (ICU). Retrospective chart review of patients > or =85 years admitted to the ICU. We recorded age, sex, previous medical history, primary diagnosis, date of admission and discharge or death, APACHE II score on admission, use of mechanical ventilation and inotropics, and complications during ICU admission. 104 patients > or =85 years (1.3% of all ICU admissions) were studied. The ICU and in-hospital mortality rates for these patients were 22 and 36% respectively. Factors correlated with a greater in-hospital mortality were: an admission diagnosis of acute respiratory failure (chi2; P = 0.007), the use of mechanical ventilation (chi2; P = 0.00005) and inotropes (chi2; P = 0.00001), complications during ICU admission (chi2; P = 0.004), in particular acute renal failure (chi2; P = 0.005), and an APACHE II score > or =25 (chi2; P = 0.001). The APACHE II scoring system and the use of inotropes were independently correlated with mortality. ICU and in-hospital mortality are higher in very elderly patients, particularly in those with an APACHE II score > or =25. The most important predictors of mortality are the use of inotropes and the severity of the acute illness.


Associations between oral hygiene habits, diet, tobacco and alcohol and risk of oral cancer: A case-control study from India.
This study examines the association between the incidence of oral cancer in India and oral hygiene habits, diet, chewing and smoking tobacco, and drinking alcohol. We also assessed the effects of oral hygiene habits with oral cancer risk among chewers versus never chewers. A hospital-based case-control study was conducted in Pune, India, based on face-to-face interviews, anthropometry, and intra-oral examinations conducted for 187 oral cancer cases and 240 controls. Poor oral hygiene score was associated with a significant risk of oral cancer (adjusted OR=6.98; 95%CI 3.72-13.05). When stratified by tobacco-chewing habit, the poor oral hygiene score was a significant risk factor only among ever tobacco chewers (adjusted OR=14.74; 95%CI 6.49-33.46) compared with never chewers (adjusted OR=0.71; 95%CI 0.14-3.63). Dental check-ups only at the time of pain by ever-chewers with poor oral hygiene was associated with an elevated risk (adjusted OR=4.22; 95%CI 2.44-7.29), while consumption of green, yellow, and cruciferous vegetables and citrus fruits was protective. A linear dose-response association was observed between oral cancer and chewing tobacco in terms of age at initiation, duration, and frequency of chewing per day (P<0.001). Smoking more than 10 bidis/cigarettes per day (adjusted OR=2.74; 95%CI 1.28-5.89) and for a duration >25 years (adjusted OR=2.31; 95%CI 1.14-4.71) elevated the risk of oral cancer. Good oral hygiene habits - as characterized by healthy gums, brushing more than once daily, use of toothpaste, annual dental check-ups, and a minimal number of missing teeth - can reduce the risk of oral cancer significantly. In addition to refraining from chewing/smoking tobacco, a diet adequate in fruits and vegetables may protect against the disease.


Brain asymmetry is globally different in males and females: exploring cortical volume, area, thickness, and mean curvature.
Brain asymmetry is a cornerstone in the development of higher-level cognition, but it is unclear whether and how it differs in males and females. Asymmetry has been investigated using the laterality index, which compares homologous regions as pairwise weighted differences between the left and the right hemisphere. However, if asymmetry differences between males and females are global instead of pairwise, involving proportions between multiple brain areas, novel methodological tools are needed to evaluate them. Here, we used the Amsterdam Open MRI collection to investigate sexual dimorphism in brain asymmetry by comparing laterality index with the distance index, which is a global measure of differences within and across hemispheres, and with the subtraction index, which compares pairwise raw values in the left and right hemisphere. Machine learning models, robustness tests, and group analyses of cortical volume, area, thickness, and mean curvature revealed that, of the three indices, distance index was the most successful biomarker of sexual dimorphism. These findings suggest that left-right asymmetry in males and females involves global coherence rather than pairwise contrasts. Further studies are needed to investigate the biological basis of local and global asymmetry based on growth patterns under genetic, hormonal, and environmental factors.


Choice-Process Satisfaction: The Influence of Attribute Alignability and Option Limitation.
This research investigates how choice-process satisfaction is influenced by limitation of choice option and by the types of features used to represent the options. Studies of choice satisfaction have focused on how satisfied the decision maker feels about the choice that has been made and have overlooked the importance of the process through which the decision maker makes a choice, i.e., choice-process satisfaction. We show that the comparability of choice options through alignable features increases choice-process satisfaction, whereas option limitation (i.e., making one option unavailable from a set of equally attractive options) decreases choice-process satisfaction. Further, this decrease in satisfaction, relative to all options being available, occurs for people who are given a set of options in which the difference features are alignable (i.e., differences of a corresponding dimension) but not for people who are given a set of options in which the difference features are nonalignable (i.e., differences of unique dimensions). We propose that alignable differences are easier to compare and have more weight in people's attribute processing, and thus give rise to a perception of a greater amount of information about the option set that is relevant for choice. Making an option unavailable in this case would have a bigger impact than in a situation in which all options have nonalignable differences. Nonalignable differences are difficult to process and are less likely to make people aware that there is very much information about the options for decision making. This explanation and the interaction effect between option limitation and feature alignability are tested in four experiments. Copyright 1999 Academic Press.


The historiography of medical history: from great men to archaeology.
The history of medicine is always written from the basis of the historian. Contemporary historiography provides an understanding of the major methods of historical analysis and their influences on the writing of medical history. Medical history in the 20th century has emphasized the historiographic methods of the history of great men, historicism, social history, and intellectual history. Each methodology has inherent biases that influence the historian's analysis of the past. Understanding the historian's biases provides the reader important tools for the interpretation of medical history.


Assessment of risk factor profile in young patients undergoing elective coronary artery bypass grafting surgery in Armed Forces Institute of Cardiology/National Institute of Heart Disease, a tertiary care cardiac facility.
To identify modifiable and non-modifiable risk factors among young patients undergoing elective coronary artery bypass graft surgery. The descriptive cross-sectional study was conducted at the Department of Adult Cardiac Surgery of the Armed Forces Institute of Cardiology and National Institute of Heart Disease, Rawalpindi, Pakistan, from January 1, 2015, to April 24, 2018, and comprised patients who underwent elective coronary artery bypass grafting. Data was collected using a predesigned questionnaire, and the risk factors studied were hypertension, diabetes, smoking, serum cholesterol, family history and body mass index. Data was analysed using SPSS 23. Of the 1270 patients, 838(66.1%) were males and 432(33.9%) were females. The overall mean age was 39.29±8.64 years (range: 18-49 years). Of the total, 319(25.2%) patients were hypertensive; 170(13.3%) were diabetics; 303(23.9%) had history of smoking; 566(44.6%) were obese. There was a high prevalence of obesity, hypertension and smoking in the patients undergoing coronary artery bypass graft surgery at age <50 years.


How Rhodopsin Tunes the Equilibrium between Protonated and Deprotonated Forms of the Retinal Chromophore.
Rhodopsin is a photoactive G-protein-coupled receptor (GPCR) that converts dim light into a signal for the brain, leading to eyesight. Full activation of this GPCR is achieved after passing through several steps of the protein's photoactivation pathway. Key events of rhodopsin activation are the initial cis-trans photoisomerization of the covalently bound retinal moiety followed by conformational rearrangements and deprotonation of the chromophore's protonated Schiff base (PSB), which ultimately lead to full activation in the meta II state. PSB deprotonation is crucial for achieving full activation of rhodopsin; however, the specific structural rearrangements that have to take place to induce this pKa shift are not well understood. Classical molecular dynamics (MD) simulations were employed to identify intermediate states after the cis-trans isomerization of rhodopsin's retinal moiety. In order to select the intermediate state in which PSB deprotonation is experimentally known to occur, the validity of the intermediate configurations was checked through an evaluation of the optical properties in comparison with experiment. Subsequently, the selected state was used to investigate the molecular factors that enable PSB deprotonation at body temperature to obtain a better understanding of the difference between the protonated and the deprotonated state of the chromophore. To this end, the deprotonation reaction has been investigated by applying QM/MM MD simulations in combination with thermodynamic integration. The study shows that, compared to the inactive 11-cis-retinal case, trans-retinal rhodopsin is able to undergo PSB deprotonation due to a change in the conformation of the retinal and a consequent alteration in the hydrogen-bond (HB) network in which PSB and the counterion Glu113 are embedded. Besides the retinal moiety and Glu113, also two water molecules as well as Thr94 and Gly90 that are related to congenital night blindness are part of this essential HB network.


Randomized sham-controlled trial of the 6-month swallowable gas-filled intragastric balloon system for weight loss.
Obesity is a significant health problem and additional therapies are needed to improve obesity treatment. Determine the efficacy and safety of a 6-month swallowable gas-filled intragastric balloon system for weight loss. Fifteen academic and private practice centers in the United States. This was a double-blind, randomized sham-controlled trial of the swallowable gas-filled intragastric balloon system plus lifestyle therapy compared with lifestyle therapy alone for weight loss at 6 months in participants aged 22 to 60 years with body mass index 30 to 40 kg/m2, across 15 sites in the United States. The following endpoints were included: difference in percent total weight loss in treatment group versus control group was >2.1%, and a responder rate of >35% in the treatment group. Three hundred eighty-seven patients swallowed at least 1 capsule. Of participants, 93.3% completed all 24 weeks of blinded study testing. Nonserious adverse events occurred in 91.1% of patients, but only .4% were severe. One bleeding ulcer and 1 balloon deflation occurred. In analysis of patients who completed treatment, the treatment and control groups achieved 7.1 ± 5.0% and 3.6 ± 5.1% total weight loss, respectively, and a mean difference of 3.5% (P = .0085). Total weight loss in treatment and control groups were 7.1 ± 5.3 and 3.6 ± 5.1 kg (P < .0001), and body mass index change in the treatment and control groups were 2.5 ± 1.8 and 1.3 ± 1.8 kg/m2 (P < .0001), respectively. The responder rate in the treatment group was 66.7% (P < .0001). Weight loss maintenance in the treatment group was 88.5% at 48 weeks. Treatment with lifestyle therapy and the 6-month swallowable gas-filled intragastric balloon system was safe and resulted in twice as much weight loss compared with a sham control, with high weight loss maintenance at 48 weeks.


Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone-related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor.
Chondrogenesis and endochondral ossification are precisely controlled by cellular interactions with surrounding matrix proteins and growth factors that mediate cellular signaling pathways. Here, we report that extracellular matrix protein 1 (ECM1) is a previously unrecognized regulator of chondrogenesis. ECM1 is induced in the course of chondrogenesis and its expression in chondrocytes strictly depends on parathyroid hormone-related peptide (PTHrP) signaling pathway. Overexpression of ECM1 suppresses, whereas suppression of ECM1 enhances, chondrocyte differentiation and hypertrophy in vitro and ex vivo In addition, target transgene of ECM1 in chondrocytes or osteoblasts in mice leads to striking defects in cartilage development and endochondral bone formation. Of importance, ECM1 seems to be critical for PTHrP action in chondrogenesis, as blockage of ECM1 nearly abolishes PTHrP regulation of chondrocyte hypertrophy, and overexpression of ECM1 rescues disorganized growth plates of PTHrP-null mice. Furthermore, ECM1 and progranulin chondrogenic growth factor constitute an interaction network and act in concert in the regulation of chondrogenesis.-Kong, L., Zhao, Y.-P., Tian, Q.-Y., Feng, J.-Q., Kobayashi, T., Merregaert, J., Liu, C.-J. Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone-related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor.


Analysis of the Influencing Factors of Sentinel Lymph Node Metastasis in Breast Cancer.
To analyze and discuss the influencing factors of sentinel lymph node metastasis in breast cancer. A total of 469 breast cancer patients admitted in the Department of Pathology of Guangdong Women and Children Hospital from October 2016 to December 2021 were retrospectively analyzed. The general information, immunohistochemical expression, tumor molecular subtype, tumor size, histological grade, pathological type, and tumor location were collected and the relationship with sentinel lymph node metastasis was analyzed. For patients with different age, Ki-67 and Human epidermal growth factor receptor-2 (HER-2) immunohistochemical expression level (invasive cancer), molecular subtype (invasive cancer), tumor size, histological grade (invasive cancer) and pathological type. The results of multivariate logistic regression analysis showed that the age was less than or equal to 40 years; the molecular subtype was Luminal B and HER-2 overexpression (invasive cancer); tumor was larger; the histological grade (invasive cancer) was higher; the pathological type was invasive carcinoma, there were independent risk factors for sentinel lymph node metastasis in breast cancer. The sentinel lymph node metastasis rates of invasive lobular carcinoma, invasive micropapillary carcinoma, and metaplastic carcinoma (all met the criteria for squamous cell carcinoma and histological grade III) were higher than 50% in special invasive carcinomas. Age, expression level of Ki 67 and HER-2, molecular typing, tumor volume and histological grade are all high-risk factors related to sentinel lymph node metastasis of breast cancer. When one or more of the above factors are involved in an examination, pathologists should be more cautious in making a sentinel lymph node frozen diagnosis. By standardizing the sampling and increasing the number of frozen sections (slicing more frozen tissue layers), the section quality can be improved. This may be conducive to reducing the false negative rate and reducing the pain and risk of secondary surgery.


Scanning laser optical tomography for in toto imaging of the murine cochlea.
The mammalian cochlea is a complex macroscopic structure due to its helical shape and the microscopic arrangements of the individual layers of cells. To improve the outcomes of hearing restoration in deaf patients, it is important to understand the anatomic structure and composition of the cochlea ex vivo. Hitherto, only one histological technique based on confocal laser scanning microscopy and optical clearing has been developed for in toto optical imaging of the murine cochlea. However, with a growing size of the specimen, e.g., human cochlea, this technique reaches its limitations. Here, we demonstrate scanning laser optical tomography (SLOT) as a valuable imaging technique to visualize the murine cochlea in toto without any physical slicing. This technique can also be applied in larger specimens up to cm3 such as the human cochlea. Furthermore, immunolabeling allows visualization of inner hair cells (otoferlin) or spiral ganglion cells (neurofilament) within the whole cochlea. After image reconstruction, the 3D dataset was used for digital segmentation of the labeled region. As a result, quantitative analysis of position, length and curvature of the labeled region was possible. This is of high interest in order to understand the interaction of cochlear implants (CI) and cells in more detail.


Immiscible Viscous Fingering: The Simulation of Tertiary Polymer Displacements of Viscous Oils in 2D Slab Floods.
Immiscible viscous fingering in porous media occurs when a high viscosity fluid is displaced by an immiscible low viscosity fluid. This paper extends a recent development in the modelling of immiscible viscous fingering to directly simulate experimental floods where the viscosity of the aqueous displacing fluid was increased (by the addition of aqueous polymer) after a period of low viscosity water injection. This is referred to as tertiary polymer flooding, and the objective of this process is to increase the displacement of oil from the system. Experimental results from the literature showed the very surprising observation that the tertiary injection of a modest polymer viscosity could give astonishingly high incremental oil recoveries (IR) of ≥100% even for viscous oils of 7000 mPa.s. This work seeks to both explain and predict these results using recent modelling developments. For the 4 cases (µo/µw of 474 to 7000) simulated in this paper, finger patterns are in line with those observed using X-ray imaging of the sandstone slab floods. In particular, the formation of an oil bank on tertiary polymer injection is very well reproduced and the incremental oil response and water cut drops induced by the polymer are very well predicted. The simulations strongly support our earlier claim that this increase in incremental oil displacement cannot be explained solely by a viscous "extended Buckley-Leverett" (BL) linear displacement effect; referred to in the literature simply as "mobility control". This large response is the combination of this effect (BL) along with a viscous crossflow (VX) mechanism, with the latter VX effect being the major contributor to the recovery mechanism.


TASUKE+: a web-based platform for exploring genome-wide association studies results and large-scale resequencing data.
Recent revolutionary advancements in sequencing technologies have made it possible to obtain mass quantities of genome-scale sequence data in a cost-effective manner and have drastically altered molecular biological studies. To utilize these sequence data, genome-wide association studies (GWASs) have become increasingly important. Hence, there is an urgent need to develop a visualization tool that enables efficient data retrieval, integration of GWAS results with diverse information and rapid public release of such large-scale genotypic and phenotypic data. We developed a web-based genome browser TASUKE+ (https://tasuke.dna.affrc.go.jp/), which is equipped with the following functions: (i) interactive GWAS results visualization with genome resequencing data and annotation information, (ii) PCR primer design, (iii) phylogenetic tree reconstruction and (iv) data sharing via the web. GWAS results can be displayed in parallel with polymorphism data, read depths and annotation information in an interactive and scalable manner. Users can design PCR primers for polymorphic sites of interest. In addition, a molecular phylogenetic tree of any region can be reconstructed so that the overall relationship among the examined genomes can be understood intuitively at a glance. All functions are implemented through user-friendly web-based interfaces so that researchers can easily share data with collaborators in remote places without extensive bioinformatics knowledge.


Below the surface: Parents' views on the factors that influence treatment adherence in paediatric burn scar management - A qualitative study.
Parents have a crucial role to play in burn scar management for their children at a time that is extremely stressful for them and their child. Scar management treatments such as pressure garment therapy (PGT) require high levels of adherence. There has been a lack of research into the factors that may influence adherence in paediatric burn scar management. This qualitative research study has investigated parents' experiences of scar management and their attempts to adhere to treatment at home. The aim of this paper is to outline parents' views on the factors that influence adherence. 25 parents of paediatric and adolescent burn patients took part in semi-structured interviews. Participants were recruited from three UK burns services. Interviews were conducted in a participant-focussed manner and topics for discussion included parents' accounts of treatment and their experience of PGT. A thematic analysis was undertaken. Four overarching themes describe parents' views and experiences of scar management and adherence. These are the transition from hospital to home; the practical realities of treatment; the emotional labour involved in treatment and; negotiating treatment and regime. The transition from hospital to home is a significant event for parents. They may be apprehensive about this at the same time as they desire that they and their child return to some sense of normality following the burn injury. Parents are required to adopt the role of therapeutic caregiver upon transition from hospital to home. Adherence to scar management is influenced by the practical realities of maintaining treatment (routine, division of care labour, hospital appointments) and the emotional labour involved in doing so. The latter demands that parents manage their own and their children's emotions. Approaches to adherence were often described as flexible in response to these influences. Some parents negotiate the realities and demands of scar management successfully, whereas others do not. The emotional labour experienced by parents and their ability to cope with this is often a strong influence on their views regarding adherence to scar management. Further research is needed to explore how burns services and staff manage this at present, and whether simple interventions can help with the key practical and emotional influences on treatment adherence.


Case Report: Surgical Treatment of High-Flow Coronary Fistulas for the Pulmonary Artery.
Coronary fistulas are rare anomalies that can affect approximately 1% of the population, presenting few specific symptoms, and are often found occasionally in coronary angiography. Here we describe the case of a 61-year-old patient with complaints of precordialgia and dyspnea since adolescence, with late diagnosis of coronary fistulas with drainage to the pulmonary artery, and with unsuccessful percutaneous treatment. Therefore, she underwent open surgery for the correction of the already known fistulas, in addition to the hemangioma involving such vessels, which made the understanding and resolution of this case more complex.


Integration of nematology as a training and research discipline in sub-Saharan Africa: progress and prospects.
Within sub-Saharan Africa (SSA), although nematodes are viewed among the most important threats to crop production and food security, the presence of trained nematologists working within this discipline has traditionally been viewed as scarce. The few research studies concerning this subject address this topic from a country or sub-regional perspective and generally portray nematology as 'insufficient'. Over the past two decades, a few initiatives have been instrumental in building greater nematology expertise. For the first time a structured survey was undertaken, involving interviews with individuals from SSA that were (or currently are) involved in nematology training programmes, research, national extension services or in African universities. This paper provides evidence of the positive impact of various initiatives and shows an increase in the number of available nematology positions, together with high rates of graduates that return home to occupy qualified positions. Our findings will help researchers, policy makers and donors to identify areas requiring support to increase the promotion of nematology in SSA and to make an impact for end-users.


Diastereoselective synthesis of 3,3-disubstituted 3-nitro-4-chromanone derivatives as potential antitumor agents.
We report an efficient and highly diastereoselective protocol for the rapid construction of 3-nitro substituted 4-chromanones by an intramolecular Michael-type cyclization of α-nitro aryl ketones bearing unsaturated ester units. A catalytic amount of KOtBu was found to be crucial for the high diastereoselective control of this transformation. With this protocol, a series of 3,3-disubstituted 3-nitro-4-chromanones were synthesized in good to excellent yields with high diastereoselectivities and showed moderate to good in vitro antitumor activities, representing promising antitumor hits for further drug discovery.


Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as first-line treatment in advanced colorectal cancer.
Capecitabine and oxaliplatin, two new agents with potential synergistic activity, have demonstrated promising antitumor efficacy in advanced colorectal cancer (ACC). Preclinical and clinical evidence indicating that dose intensification of the oral fluorouracil prodrug might result in improved therapeutic results led us to the present randomized multicenter phase II study. Eighty-nine patients with bidimensionally measurable ACC previously untreated for metastatic disease were randomly allocated to receive oxaliplatin 130 mg/m(2) day 1 plus capecitabine 2,000 mg/m(2)/d days 1 to 14 every 3 weeks (arm A) or to receive oxaliplatin 85 mg/m(2) days 1 and 14 combined with capecitabine 3,500 mg/m(2) days 1 to 7 and 14 to 21 every 4 weeks (arm B). In both treatment arms, chemotherapy was continued for a total of 6 months unless there was prior evidence of progression of disease. Patients allocated to the high-dose capecitabine combination arm B had a higher radiologically confirmed response rate (54.5% v 42.2%) and a significantly longer median progression-free survival time than those allocated to control arm A (10.5 v 6.0 months; P =.0013). Median overall survival times cannot be calculated for either treatment arm at this point. Despite a 34% higher dose intensity of capecitabine in arm B, there was no difference in hematologic toxicity between treatment arms (neutropenia/thrombocytopenia: 60%/43% in arm B v 56%/33% in arm A). Similarly, the incidence rate and degree of nonhematologic adverse events were comparable: The most commonly encountered symptoms (all grades, arm A and arm B) included nausea/emesis (A: 58%; B: 62%), diarrhea (A: 44%; B: 31%), peripheral sensory neuropathy (A: 80%; B: 83%), and fatigue (A: 40%; B: 50%). Results of this study indicate that both combination regimens are feasible, tolerable, and clinically active. The dose-intensified bimonthly capecitabine arm, however, seems to be more effective in increasing both response rate and progression-free survival time.


Cationic surfactants for micellar electrokinetic chromatography: 1. Characterization of selectivity using the linear solvation energy relationships model.
MEKC and the linear solvation energy relationship (LSER) model have been applied to two series of cationic surfactants. The synthetic flexibility of the quaternary ammonium group is exploited to generate the two series, one consisting of linear substitutions and the other incorporating the ammonium into ring structures of varying size. The effects of the head group structure on the CMC, aggregation number, and electrophoretic properties of the surfactants were determined. These surfactants were also characterized with the LSER model, which allowed the contributions of five chemical factors to the interactions between solutes and the micelles to be evaluated. Trends were observed in the cohesivity and polarity of the linear surfactant series, with both increasing with the size of the head group. No trends in the LSER parameters were observed in the cyclic series, but the LSER results do show that the surfactants with cyclic head groups provide a significantly different solvation environment from the linear series. Additional trends were observed in the aggregation behavior and chromatographic properties of the surfactants. These included changes in the CMCs, aggregation numbers, EOF, and electrophoretic mobility of the micelles that correlate to changes in head group size.


An analysis of the HIV testing cascade of a group of HIV-exposed infants from birth to 18 months in peri-urban Khayelitsha, South Africa.
Despite the reduction of HIV mother-to-child transmission, there are concerns regarding transmission rate in the breastfeeding period. We describe the routine uptake of 6 or 10 (6/10) weeks, 9 months and 18 months testing, with and without tracing, in a cohort of infants who received HIV PCR testing at birth (birth PCR) (with and without point of care (POC) testing) in a peri-urban primary health care setting in Khayelitsha, South Africa. In this cohort study conducted between November 2014 and February 2018, HIV-positive mothers and their HIV-exposed babies were recruited at birth and all babies were tested with birth PCR. Results of routine 6/10 weeks PCR, 9 months and 18 months testing were followed up by a patient tracer. We compared testing at 6/10 weeks with a subgroup from historical cohort who was not tested with birth PCR. We found that the uptake of 6/10 weeks testing was 77%, compared to 82% with tracing. When including all infants in the cascade and comparing to a historical cohort without birth testing, we found that infants who tested a birth were 22% more likely to have a 6/10 weeks test compared to those not tested at birth. There was no significant difference between the uptake of 6/10 weeks testing after birth PCR POC versus birth PCR testing without POC. Uptake of 9 months and 18 months testing was 39% and 24% respectively. With intense tracing efforts, uptake increased to 45% and 34% respectively. Uptake of HIV testing for HIV-exposed uninfected infants in the first 18 months of life shows good completion of the 6/10 weeks PCR but suboptimal uptake of HIV testing at 9 months and 18 months, despite tracing efforts. Birth PCR testing did not negatively affect uptake of the 6/10 weeks HIV test compared to no birth PCR testing.


[Specificity of carp antihuman myeloma protein sera depending on the holding temperature].
While in carps kept in warm water (28 degrees C) and immunized with a human myeloma protein a challenge leads to an increase, the antibody titres in carps kept in cold water (14 degrees C) are changed only unsignificantly. Antibody titres of carps immunized once respectively three times and kept in cold water are not markedly different. In testing the specificity of the antisera taken from each of the three groups no differences could be recognized. With carp anti-IgGZei sera using the passive hemagglutination inhibition test a paraprotein characterizing determinant (s) is just as well demonstrable as by using a rabbit antiserum.


Small airways in asthma: from bench-to-bedside.
Historically, asthma was considered a disease predominantly of the large airways, but gradually small airways have been recognized as the major site of airflow obstruction. Small airway dysfunction (SAD) significantly contributes to the pathophysiology of asthma, and it is present across all asthma severities. Promising preclinical findings documented enhanced beneficial effects of combination therapies on small airways compared to monocomponents, thus it was questioned whether this could translate into further clinical implications from bench-to-bedside. The aim of this review was to systematically assess the state of the art of small airway involvement in asthma, especially in response to different pharmacological treatments acting on the respiratory system. A comprehensive literature search was performed in MEDLINE for randomized controlled trials (RCTs) characterizing the impact on small airways of different pharmacological treatments acting on the respiratory system. The results were extracted and reported via qualitative synthesis. Overall, 63 studies were identified from the literature search, whereas 23 RCTs met the inclusion criteria. Evidence confirms that both drug particle size and the type of inhalation devices represent two of the most important variables for an effective peripheral lung distribution. Despite the numerous methodological tools to detect SAD, there is still no gold standard diagnostic method to assess small airways, especially in severe asthma. Further research should be directed to improve primary and secondary prevention strategies by supporting the combined approach of different non-invasive techniques for an early detection of peripheral abnormalities and optimization of asthma therapy.


Sleep with Open Eyes in Two Species of Deer, the Indian Sambar (Rusa unicolor) and Sika Deer (Cervus nippon).
The relationship between postures, sleep stages and eye state was established in two species of deer, the Indian sambar (Rusa unicolor) and sika deer (Cervus nippon), based on video recording. In both species, the state of rest or behavioral sleep was recorded in the sternal position, holding the head above the ground, and in the lateral position, with the head resting on the croup or on the ground. Rest accounted for at least 80% of the time in these positions. Based on behavior criteria a substantial portion of rest represented slow-wave sleep. Episodes of rapid eye movements (REM sleep) were recorded in the lateral position. They did not exceed 2 min. When the deer were in the sternal posture, they kept their eyes open most of the time: in average 96% of the time in sambars and 82% in sika deer. Episodes of the open eye in this posture lasted up to 8.4 min in sambars and up to 3.3 min in sika deer. In the lateral position, such episodes were 4 and 1.5 times shorter. Sleeping with open eyes in ungulates may be an important mechanism of maintaining vigilance.


Response to deep hypoglycemia does not involve glucoreceptors in carotid perfused tissue.
In the present study we examined whether the magnified hormonal counter-regulatory response seen during deep hypoglycemia (40 mg/dl) could be attenuated by supplying the forebrain with glucose furnished through carotid infusion. Two protocols were performed in conscious dogs. In the first protocol we infused glucose bilaterally into the carotid circulation to produce a forebrain glycemia of 55 +/- 1 mg/dl (as reflected in the jugular vein), whereas systemic glycemia declined to 39 +/- 2 mg/dl. In the second protocol as a control we infused glucose into the systemic circulation at a rate matched to protocol 1 so that both systemic and jugular plasma glucose concentrations were equivalent to the systemic glucose concentrations in protocol 1 (jugular, 41 +/- 3 mg/dl; systemic, 40 +/- 2 mg/dl; P greater than 0.9). In spite of a substantial difference in forebrain glycemia (55 mg/dl compared with 41 mg/dl) there were no differences in the counter-regulatory responses of catecholamines or glucagon. In addition, through the use of radiolabeled microspheres, we defined the precise regions of the forebrain irrigated during bilateral intracarotid glucose infusions. The concentration of microspheres was high in the forebrain but very low in the hindbrain. Our results indicate that glucoreceptor cells in tissues perfused by carotid arteries may play a tautological role in the sympathetic response to hypoglycemia and imply that glucose-sensitive receptors must also be located elsewhere in the central nervous system or in the periphery.


Impact of hepatitis B vaccination on hepatitis B disease and nucleic acid testing in high-prevalence populations.
Hepatitis B virus (HBV) infection is highly prevalent in Asia, Africa, southern Europe and Latin America, HBV vaccination has effectively reduced the acute and chronic infection rates as well as related complications in the vaccinated children. The incidence of hepatocellular carcinoma in children has been reduced to approximately 25% of the incidence before the vaccination program, and fulminant hepatitis in children has also been reduced after universal hepatitis B vaccination. HBV DNA sero-positive rate was 98-100% in HBsAg positive vaccinated children, while the positive rate was only 11-20% in those vaccinees with a negative HBsAg but positive anti-HBc reaction. Hepatitis B surface gene mutants in HBV DNA positive children increased gradually from 7.8% before the vaccination program, to 19.6%, 28.1% and 23.1% at 5, 10 and 15 years after the vaccination program. Long-term follow-up of vaccinated children has confirmed that universal HBV vaccination in infancy has produced adequate protection up to 14 years of age. The annual decay rate of hepatitis B surface antibody (anti-HBs) was 10.2% in children who did not receive a booster dose. The new HBV infection rate was not different between those who did and those who did not receive a booster dose of HBV vaccine. During a follow-up period of seven years for 1200 vaccinated 7-year-old children in Taiwan, the mean annual hepatitis B core antibody sero-conversion rate was 0.2%. All were negative for HBV DNA. No new chronic HBV infections developed. A booster dose of HBV vaccine is not recommended in children under 15 years of age. Systematic HBV DNA screening of a large population such as blood donors may be instrumental in following the long-term effect of the universal vaccination program on the incidence of silent HBV infection and vaccine escape mutants.


Transcription of the HXT4 gene is regulated by Gcr1p and Gcr2p in the yeast S. cerevisiae.
Glucose transport and glycolysis are two sequential events which are regulated by both physiological and environmental signals in the yeast Saccharomyces cerevisiae. Transcription of the HXT4 gene was found to be regulated by Gcr1p and Gcr2p, transcription factors that are required for the regulated high level transcriptions of glycolytic genes. Transcription of HXT4 decreased about 35-fold in gcr1 mutant and two-fold in gcr2 mutant yeast cells. However, transcription of other HXT genes was not affected at a significant level by gcr1 or gcr2 mutations. Overproduction of Gcr1p from an inducible promoter resulted in a 15-64% increase in transcription of HXT4, depending on the growth conditions. Gel mobility shift assays performed with the purified DNA binding domain of Gcr1p and the UAS region of the HXT4 gene showed that Gcr1p interacts directly with multiple sites on the HXT4 UAS region. These results indicate that Gcr1p and Gcr2p coordinate the transcription of HXT4 and glycolytic genes.


Quantum Hall Effect across Graphene Grain Boundary.
Charge carrier scattering at grain boundaries (GBs) in a chemical vapor deposition (CVD) graphene reduces the carrier mobility and degrades the performance of the graphene device, which is expected to affect the quantum Hall effect (QHE). This study investigated the influence of individual GBs on the QH state at different stitching angles of the GB in a monolayer CVD graphene. The measured voltage probes of the equipotential line in the QH state showed that the longitudinal resistance (Rxx) was affected by the scattering of the GB only in the low carrier concentration region, and the standard QHE of a monolayer graphene was observed regardless of the stitching angle of the GB. In addition, a controlled device with an added metal bar placed in the middle of the Hall bar configuration was introduced. Despite the fact that the equipotential lines in the controlled device were broken by the additional metal bar, only the Rxx was affected by nonzero resistance, whereas the Hall resistance (Rxy) revealed the well-quantized plateaus in the QH state. Thus, our study clarifies the effect of individual GBs on the QH states of graphenes.


Fumonisin B1 contamination in breast milk and its exposure in infants under 6 months of age in Rombo, Northern Tanzania.
The carry-over of fumonisin B1 from contaminated feed into dairy milk also suggests its carry-over from contaminated food into breast milk. This study assessed fumonisin B1 contamination in breast milk and associated exposures of infants under 6 months of age. Breast milk samples were collected from 131 lactating mothers and the weight of their infants was measured during the first month of lactation. Fumonisin B1 was extracted using methanol:acetone, cleaned up with Strong Anion Exchange columns and quantified by HPLC. Fumonisin B1 exposure in each child was estimated using deterministic approach. Out of the 131 samples, 58 (44.3%) contained fumonisin B1 at levels ranging from 6.57 to 471.05 ng/ml. Of the contaminated samples, 10.3% had fumonisin B1 levels above the EU limit of 200 ppb for fumonisins in infants' food. Exposure in the infants ranged from 0.78 to 64.93 µg/kg body weight (bw) per day (median, 3 µg/kg bw/day) and exceeded the provisional maximum tolerable limit of 2 µg/kg bw/day in 29% of the infants. In conclusion, breast milk from mothers in Northern Tanzania is contaminated with fumonisins at levels that lead to unacceptable exposures in infants. Strategies to prevent lactating mothers from fumonisin exposure are urgently needed to minimise fumonisin exposure in infants.


The last six months of life for patients with congestive heart failure.
To characterize the experiences of patients with congestive heart failure (CHF) during their last 6 months of life. A retrospective analysis of data from a prospective cohort study. Five geographically diverse tertiary care academic medical centers. A total of 1404 patients enrolled in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT) with a diagnosis of an acute exacerbation of CHF, of whom 539 patients died within 1 year of their index hospitalization. Data from interviews with patients or their surrogates were collected and chart abstractions performed at several time points in SUPPORT. To describe progression to death, we constructed four observational windows backward in time, beginning with patients' dates of death and ending with their date of entry into the SUPPORT project or 6 months before death, whichever came first. For each outcome, patients contributed information to all windows for which they had data collected. We describe frequency distributions for each outcome over time and report tests for trend. Outcomes examined over time included: percentage of days spent in a hospital; model-based prognostic estimates of 6-month survival; functional status; occurrence of severe physical and emotional symptoms, including pain, depression and anxiety; patients' preferences for care; and the financial impact of patients' illnesses on their families. As death approached, patients' prognoses became poorer and illnesses more severe. Median Acute Physiology Scores for hospitalized patients rose from 33 in the interval 6 months to 3 months before death, to 44 within 3 days of death. However, the median model-based estimate of 6-month survival was 54% even within 3 days of death. Number of functional impairments, median depression scores and percent of patients reporting severe pain or dyspnea increased as death approached, with 41% of patient surrogates reporting that the patient was in severe pain and 63% reporting that the patient was severely short of breath during the 3 days before death. Perceived quality of life did not change appreciably, with 29 to 58 % of patients reporting good to excellent quality of life in all intervals before death. As death approached, patients were more likely to prefer Do Not Resuscitate (DNR) status, with the percent of patients preferring DNR rising from 33% at 6 months to 3 months before death to 47% at 1 month to 3 days before death (P < .05). The frequency with which DNR orders were written for hospitalized patients also increased as death approached. The patients' illnesses had marked financial impact on their families, with 23 % of patients' families reporting the loss of most or all of family savings at the time of the patient's death. As death approaches during the last 6 months of life in CHF, illness becomes more severe, disability and the experience of certain symptoms more frequent, and patient preference not to be resuscitated more common. However, there is no significant decrement in quality of life as death approaches. Reflecting the unpredictable course of CHF during the last month of life, many patients have good median model-based 6-month prognoses and enjoy good to excellent quality of life.


[Indicators of the atherogenic properties of plasma lipoproteins and coronary atherosclerosis (selective angiography data)].
A combined study of possible atherogenic factors was carried out in 213 males subjected to clinical investigation including selective angiography of the heart's coronary arteries. Two sets of biochemical tests were used: the routine set including the measurement of the plasma lipid spectrum, and a more sophisticated procedure (93 cases) where plasma apoproteins A1 and B, and high-density lipoprotein phospholipid composition were assessed as well. A correlation of biochemical disorders to coronary atherosclerosis could be demonstrated in 68% of cases, using the first set, and in 98% with the second set. Abnormal apoprotein levels and high-density lipoprotein phospholipid composition were found to contribute significantly to lipoprotein atherogenesis even in cases of normolipidemia.


Dual-wavelength-pumping of mid-infrared Tm:YLF laser at 2.3 µm: demonstration of pump seeding and recycling processes.
Upconversion pumping of thulium lasers emitting around 2.3 µm (the 3H4 → 3H5 transition) has recently attracted a lot of attention as it is compatible with the mature Yb-laser technology. To explore this possibility, we built a mid-infrared Tm:LiYF4 laser pumped by an Yb:CaF2 laser at 1.05 µm delivering an output power of 110 mW at 2.31 µm for a maximum incident pump power of 2.0 W. A strong absorption issue appeared in the Tm laser: the slope efficiency vs. the incident pump power was 7.6% while that vs. the absorbed pump power reached 29%. To overcome this issue, a dual-wavelength pumping at 0.78 µm and 1.05 µm was explored (combining both the direct and upconversion pumping schemes). The reciprocal interplay between the two pumps was studied to evaluate their benefits in terms of the pump absorption and laser efficiency. We observed an interesting decrease of the laser threshold for upconversion pumping when adding a small fraction of the direct pump revealing a seeding effect for the excited-state absorption from the metastable 3F4 level. A recycling process of this manifold by excited-state absorption in the 3F4 → 3F2,3 loop was also observed. The pump absorption seeding is a viable route for the development of low-threshold upconversion pumped thulium lasers.


Magnetoencephalogram in a postoperative case with a large skull defect.
We present a patient in whom magnetoencephalograms were successfully performed in presurgical and postsurgical evaluations. A 12-year-old boy with congenital porencephaly was admitted with refractory adversive seizures and frontal absence seizures. Ictal magnetoencephalographic dipoles with frontal absence seizures were located in the left frontal lobe, anterior to the porencephalic cyst, and concordant with the same area detected by intraoperative electrocorticography. A partial cortical excision was performed, and the patient's cranial bone flap was removed because of an epidural abscess. The frontal absences then disappeared. The magnetoencephalogram revealed that secondary bilateral synchrony of focal discharges from the lesion may have caused the generalized seizures in this patient. Because of residual partial seizures, second and third magnetoencephalograms were performed, and we detected residual spike dipoles clustering in the area posterior to the cavity of cortical excision and anterior to the porencephalic cyst. Another excision of the area between the cavity and frontal edge of the cyst was performed, and seizure frequency diminished dramatically. In this case, despite the failure of dipole estimation by electroencephalogram in the context of a large bone defect, the magnetoencephalogram was useful in detecting the residual epileptogenic zone after failed epilepsy surgery.


Adherence to Oral Pre-Exposure Prophylaxis Intervention by Transgender Women: A Systematic Review.
Prevalence of human immunodeficiency virus (HIV) is higher in transgender populations. Pre-exposure prophylaxis (PrEP) intervention is successful in reducing HIV acquisition. We aimed to investigate the adherence to oral PrEP by HIV-negative transgender women (TW). We followed the Cochrane Handbook for Systematic Reviews of Interventions and the PRISMA Statement. We searched in WoS, OVID, Scopus, MEDLINE, and the Cochrane Central Register of Controlled Trials databases. Participation and adherence to the intervention were low for TW compared to cisgender men who have sex with men (cMSM), and it was measured mostly by self-report (72.7%) or tenofovir-diphosphate/emtricitabine triphosphate dried blood spot (45.5%). Awareness should increase and the effect of oral PrEP on gender-affirming hormone therapy should be explained to TW at the beginning of the trials. One limitation is that our sample size was dominated by two Thai studies with TW sex workers. Future studies should evaluate adherence to new PrEP modalities.


Bronchial provocation testing: the future.
Performing a bronchial provocation test (BPT) using a direct or indirect stimulus to identify bronchial hyper-responsiveness (BHR) reduces the possibility of over and under-diagnosis of asthma based on history and symptoms. This review discusses some long-held beliefs of BPTs to include or exclude a diagnosis of asthma or exercise-induced bronchoconstriction (EIB). A high frequency of negative methacholine tests has been reported in 240 patients given a diagnosis of asthma at the end of the study, many of whom had documented EIB. This suggests that a negative methacholine test should not be relied upon to rule out asthma. Further, a positive methacholine test alone should be interpreted with caution as it may reflect airway injury rather than asthma or EIB. Mannitol, an indirect stimulus, identified a similar prevalence of BHR to methacholine and identified more patients than a single exercise test in three studies. However, neither mannitol nor methacholine identified all patients with EIB. Mannitol has a higher specificity for a physician diagnosis of asthma than methacholine. It is likely that both a direct test and an indirect test result may be required in some patients in order to confirm or exclude a diagnosis of asthma with certainty.


Regulation of eNOS-derived superoxide by endogenous methylarginines.
The endogenous methylarginines, asymmetric dimethylarginine (ADMA) and N (G)-monomethyl- l-arginine (L-NMMA) regulate nitric oxide (NO) production from endothelial NO synthase (eNOS). Under conditions of tetrahydrobiopterin (BH 4) depletion eNOS also generates (*)O 2 (-); however, the effects of methylarginines on eNOS-derived (*)O 2 (-) generation are poorly understood. Therefore, using electron paramagnetic resonance spin trapping techniques we measured the dose-dependent effects of ADMA and L-NMMA on (*)O 2 (-) production from eNOS under conditions of BH 4 depletion. In the absence of BH 4, ADMA dose-dependently increased NOS-derived (*)O 2 (-) generation, with a maximal increase of 151% at 100 microM ADMA. L-NMMA also dose-dependently increased NOS-derived (*)O 2 (-), but to a lesser extent, demonstrating a 102% increase at 100 microM L-NMMA. Moreover, the native substrate l-arginine also increased eNOS-derived (*)O 2 (-), exhibiting a similar degree of enhancement as that observed with ADMA. Measurements of NADPH consumption from eNOS demonstrated that binding of either l-arginine or methylarginines increased the rate of NADPH oxidation. Spectrophotometric studies suggest, just as for l-arginine and L-NMMA, the binding of ADMA shifts the eNOS heme to the high-spin state, indicative of a more positive heme redox potential, enabling enhanced electron transfer from the reductase to the oxygenase site. These results demonstrate that the methylarginines can profoundly shift the balance of NO and (*)O 2 (-) generation from eNOS. These observations have important implications with regard to the therapeutic use of l-arginine and the methylarginine-NOS inhibitors in the treatment of disease.


Improving polarization squeezing in Sagnac interferometer configuration using photonic crystal fiber.
The greater confinement of light that is possible in photonic crystal fibers (PCFs) leads to greater effective nonlinearity, which promises to yield greater quantum squeezing than is possible in standard optical fiber. However, experimental work to date has not achieved improvements over standard fiber. We present a comprehensive numerical investigation of polarization squeezing in PCF in a Sagnac configuration. By including loss, a noninstantaneous Raman response, excess phase-noise, second- and third-order dispersion, and self-steepening, the simulations are able to identify the physical factors that limit current PCF squeezing experiments.


Treatment of pyogenic hepatic abscesses. Surgical vs percutaneous drainage.
A retrospective review of 39 patients with pyogenic hepatic abscess treated from 1977 through 1984 included 23 patients who were surgically treated and 16 who underwent percutaneous drainage. The average age in each group was similar (about 55 years). The most common cause of abscesses in each group was biliary tract disease. Abscesses caused by portal seeding and local extension were more common in the surgical group, 14 of whom required additional surgical procedures at the time of surgical drainage. Of the 16 patients in the percutaneously drained group, seven were seen during the immediate postoperative period. Most of the abscesses occurred in the right lobe of the liver, but single abscesses in the left lobe (30%) and multiple abscesses (57%) were more common in the surgical group. Klebsiella enterobacter and group D streptococcus were most common in the surgically and percutaneously drained groups, respectively. All patients received antibiotics, with a mean length of treatment of 14 days. Mean time to defervescence was about four days in both groups, with a longer hospital stay for the percutaneously drained group (26 vs 46 days). Morbidity was high in both groups (surgical, 48%; percutaneous, 69%). Three of the percutaneously treated patients required surgical drainage because of highly viscous abscess contents. Mortality was 17% in the surgical group and 13% in the percutaneously drained group. Percutaneous drainage with computed tomography probably should be the initial drainage procedure in patients with pyogenic hepatic abscesses in whom no concomitant surgical procedure is planned. Regardless of treatment, the morbidity and mortality remain high.


Practical considerations of intravenous sedation for the perioperative nurse.
There has been a recent increase in the number and types of cases performed with conscious sedation in the operating room and in minor operative suites (endoscopy, plastics, etc.), with nurse administering conscious sedation to healthy, uncomplicated patients under the direction of a physician. The literature is replete with articles which proffer guidelines, discuss the basics of conscious sedation, the role of the nurse, training and competency issues, and policy development. This article provides perioperative nurses with some practical, hands-on information to aid them in providing safe, quality care to their patients. There are detailed sections which address required equipment, perioperative patient assessment and monitoring, and information on commonly used medications and their side effects. The author offers this information based on literature review, education, and experience, and does not reflect the official position of any one organization.


Pulmonary blastomycosis: a new endemic area in New York state.
We describe three cases of pulmonary blastomycosis in patients from central New York State (NYS). Two of these cases occurred in 2012, and in patients who resided in the same county. Moreover, two of these cases manifested with acute respiratory distress syndrome and survived. Interestingly, one of the two received corticosteroids and was extubated within 1 week. To the best of our knowledge, these are the first cases of human blastomycosis to be reported from NYS and we propose that corticosteroids administration might reduce hospitalisation time and ventilator-associated complications, even though it is not currently recommended in standard treatment.


Effect of combined treatment with dopaminergic and GABA-ergic drugs on the threshold for maximal electroconvulsions in mice.
Aminooxyacetic acid (AOAA; 20 and 40 mg/kg), baclofen (15 and 20 mg/kg), gamma-hydroxybutyric acid (GHBA; 250 mg/kg) and gamma-aminobutyric acid (GABA: 3000 mg/kg), administered intraperitoneally, increased the convulsive threshold in mice but to a relatively small degree. Bicuculline and picrotoxin were shown to reverse these anticonvulsant effects except for baclofen. Apomorphine (10 mg/kg), amantadine (100 mg/kg) and L-DOPA (62 . 5 and 125 mg/kg) potentiated the action of AOAA (20 mg/kg). Also apomorphine (5 and 10 mg/kg) and amantadine (25 and 100 mg/kg) potentiated the anticonvulsant activity of baclofen (15 mg/kg). Combined treatment with baclofen (15 mg/kg) and amantadine (100 mg/kg) resulted in about 4-fold increase in the convulsive threshold. However, the action of GABA and GHBA was poorly affected by dopaminergic agonists, amantadine even decreased the threshold in animals pretreated with these substances. The results obtained in this study suggest dopaminergic stimulation to be of importance in potentiating the anticonvulsant action of some GABA-ergic drugs.


The Association of Loneliness with Diabetes Is Mediated by Physical Activity and BMI but Not Diet Quality.
Loneliness is considered a predictor of poor health through numerous pathways. Mediators of this association has not been extensively explored. The study objective was to determine if diet quality and physical activity are parallel mediators with body mass index (BMI) as the third mediator in the association of loneliness with diabetes. The sample, middle-aged and older African American and White adults, 36-77 years, participated in the second follow-up wave of the prospective Healthy Aging in Neighborhoods of Diversity across the Life Span study, 2013-2017. Loneliness was measured by the UCLA 3-item loneliness scale. Participants were categorized as not diabetic, pre-diabetic, or diabetic based on fasting blood glucose, self-reports, or taking medication for diabetes. The Mean Healthy Eating Index-2010 score was calculated from two 24 h dietary recalls collected using the USDA automated multiple pass method. Physical activity was derived from the Baecke questionnaire. The Hayes PROCESS macro, model #80, was used to perform the mediational analysis. Covariates were age, sex at birth, race, income, alcohol intake, and education. Loneliness was inversely and significantly associated with diet quality and physical activity. The only significant indirect path was loneliness > physical activity > BMI > diabetes. Better understanding of modifiable lifestyle behaviors when developing interventions may improve mental health, thereby improving health.


Endogenous Sex Hormones and Endothelial Function in Postmenopausal Women and Men: The Multi-Ethnic Study of Atherosclerosis.
Background: The relationship of endogenous sex hormones (SH) with vascular endothelial function and with cardiovascular disease (CVD) is incompletely understood. We examined the associations between SH and endothelial function measured by brachial artery flow-mediated dilation (FMD). Materials and Methods: We included 1368 postmenopausal women and 1707 men, free of clinical CVD, participating in MESA Visit 1 (2000-2002). Serum SH [total testosterone, SH binding globulin (SHBG), dehydroepiandrosterone (DHEA), estradiol] were measured; free testosterone was calculated. The percent FMD difference (%FMD) was measured by high-resolution ultrasound. Using multivariable-adjusted linear regression, we tested the cross-sectional associations of SH (log transformed, compared per one SD increment) with %FMD. Results: The mean age of women and men were 64.2 and 61.4 years, respectively. Among women, after adjusting for demographics, CVD risk factors, and hormone therapy, higher SHBG was associated with greater %FMD [β = 0.215% (95% CI 0.026-0.405)], whereas higher free testosterone was associated with a smaller %FMD [-0.209% (-0.402, -0.017)]. Estradiol and DHEA were not associated with %FMD in women after multivariable adjustment. There was an age interaction, with higher free testosterone and lower SHBG associated with worse FMD in women <65 years of age, but not in those ≥65 years (p = 0.04). We did not see similar associations in men. Conclusions: A more androgenic SH profile of higher free testosterone and lower SHBG was associated with worse %FMD in postmenopausal women. Changes in SH with aging and menopause may result in vascular changes in women. Further studies are needed to assess longitudinal changes in SH levels and their association with vascular function.


Plasma Protein Profiling of Incident Cardiovascular Diseases: A Multisample Evaluation.
Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs. Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure. Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% (P<0.0001) in SIMPLER when added to traditional risk factors. Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin were novel early markers of CVD. A selection of 11 proteins improved the discrimination of CVD.


Hypoxic VDAC1: a potential mitochondrial marker for cancer therapy.
Finding new therapeutic targets to fight cancer is an ongoing quest. Because of insufficiencies in tumor vasculature, cells often are exposed to a hostile microenvironment that is low in oxygen (hypoxic) and nutrients. Thus, tumor cells face the challenge of finding new sources of energy and defying apoptosis, which allow them to survive, grow, and colonize other tissues. Eradicating specifically these hypoxic cells is one of the many goals of anticancer therapies. The mitochondrial voltage-dependent anion channel (VDAC) is a protein at the crossroads of metabolic and survival pathways. As its name suggests, VDAC is involved in ion transport as well as adenosine triphosphate and NAD(+) transport. We recently reported the presence in tumor cells of a novel hypoxia-induced form of VDAC. This form, a C-terminal truncated protein (VDAC1-ΔC), was associated in some cancer cell lines with a high output of adenosine triphosphate and a strong resistance to chemotherapy-induced apoptosis. Furthermore, VDAC1-ΔC was detected in tissues of 50 % of 46 patients with lung cancer. This review examines the significance of this new form of VDAC1 for anticancer therapy.